Alpha-Hydroxy Acids: Unapproved Uses or Indications - SKINmed 2004;3(3):141–148

Marcia Ramos-e-Silva, MD, PhD; Maria Cristina Ribeiro de Castro, MD; Sueli Coelho da Silva Carneiro, MD, PhD

From the Sector of Dermatology, HUCFF-UFRJ and School of Medicine, Federal University of Rio de Janeiro, and HUPE-UERJ and School of Medicine, State University of Rio de Janeiro, Rio de Janeiro, Brazil

Alpha-hydroxy acids have been used for rejuvenation since ancient times, and now there are several on the market. Depending on the concentration, some have been shown to be effective as peeling agents and for rejuvenation. Glycolic acid and lactic acid are the α-hydroxy acids most frequently used in cosmetics, although there are many others used in combination. Some of the most striking advances in dermatology have followed the off-label use of drugs, which is widespread and unavoidable, but a well founded scientific approach to an individual patient’s pathology must be emphasized as the number of products, regimens, and adjuncts increases exponentially in the cosmetic field. In this article the authors review some unapproved uses of α-hydroxy acids. More published data on the scientific value of these off-label indications that proves whether they are effective or not is needed.

Alpha-hydroxy acids (AHAs), also called fruit acids, are carboxylic acids derived from fruit and milk sugars, although they can also be synthetically produced. 1, 2 Since ancient times, AHA has been used for rejuvenation. Cleopatra was known to bathe in sour milk, and French women used wine; both substances contain AHA. 2, 3 Actually, AHA can be easily found in numerous creams and lotions for daily use, mainly for the face. They are also found in small amounts in other cosmetics such as shampoos and cuticle softeners. 1 The best way to find out if there are AHAs in a product is to check its components. Ingredient terms that indicate that a cosmetic contains AHA and/or β-hydroxy acids (BHA) include 1, 4 : glycolic acid (GA), lactic acid, GA plus ammonium glycolate, α-hydroxyethanoic acid plus ammonium α-hydroxyethanoate, α-hydroxyoctanoic acid, α-hydroxycaprylic acid, hydroxycaprylic acid, mixed fruit acid, triple fruit acid, tri-a hydroxy fruit acids, sugarcane extract, α-hydroxy and botanical complex, L-α-hydroxy acid, glycomer in crosslinked fatty acids a nutrium (three AHAs), salicylic acid, β-hydroxybutanoic acid, tropic acid, and trethocanic acid. Although from a chemist’s perspective salicylic acid is not a true BHA, cosmetic companies often refer to it as a BHA, and consequently, many consumers think of it as one. 1 GA, an AHA, has been shown to be effective as a peeling agent and is available in a variety of strengths. 5 AHAs (glycolic, lactic, and citric acid) applied topically, at 25%, have been demonstrated to increase epidermal and papillary dermal thickness, increase acid mucopolysaccharide, improve the quality of elastic fibers, and increase the density of collagen. 6 The two acids with the shortest chain, GA and lactic acid, are also the most frequently used in cosmetics, although there are many others used in combination. 1, 2, 4

Confirmed Properties and Regular Uses

The US Food and Drug Administration (FDA) is the federal agency responsible for ensuring that foods are safe, wholesome, and sanitary; human and veterinary drugs, biological products, and medical devices are safe and effective; cosmetics are safe; and electronic products that emit radiation are safe. The FDA also ensures that these products are honestly, accurately, and informatively represented to the public. 7 Cosmetics that contain AHAs have become widely used in recent years despite many unanswered questions about their safety. 4

The FDA cautions consumers about possible hazards associated with use of chemical skin peeling products.

Since 1989, the FDA has received many reports of adverse reactions from people using AHA products. John Bailey, PhD, acting director of the FDA Office of Cosmetics and Colors, believes, “this would translate into approximately 10,000 adverse reactions being received for AHA-containing products.” 1 The complaints range from mild irritation, rash, itching, skin discoloration, severe redness, and swelling (especially in the area of the eyes) to serious injuries such as burning, blistering, bleeding, and scarring caused by skin peelers used without doctor supervision. 1, 4, 8 In reviewing the limited data on AHAs, the FDA concluded in a 1996 report that certain formulations of AHA products can affect the skin in a manner similar to that of chemical peels, that is, increasing cell turnover rate and decreasing the thickness of the outer skin. The effect depends on the product’s pH level, the AHA concentration, the AHA vehicle cream, and how the product is used (frequency of use, skin application region). 1

Recent studies for the FDA task force have demonstrated that both the efficacy and irritability of GA preparations are related to the pH/pKa and the concentration of the preparations. GA also increases the clinical efficacy of a variety of topical agents, but the mechanism of this enhanced effect is presently unknown. 9 In 1999 the only product approved by the FDA for the treatment of photodamage (fine wrinkles, mottled hyperpigmentation, and skin roughness) was topical tretinoin emollient cream. 10

The FDA intends to complete a photocarcinogenicity study of AHAs in a newly established testing facility in a study that began in 2000. 11 Meanwhile, the scientists of the National Toxicology Program and the FDA continue to study AHA safety, including the risk of cancer associated with sunlight and ultraviolet radiation. “There are many unanswered questions in front of us,” and, “the absence of action by the FDA to date does not mean that there will not be any in the future,” says Bailey. 1 Depending on the outcome of the FDA’s investigation, the agency may or may not take action against AHA products. Currently, the FDA recognizes AHA as a cosmeceutical and not as a medication.

Today the FDA cautions consumers about possible hazards associated with use of chemical skin peeling products. These products vary considerably as to their ingredients and strength. Skin reactions to the chemicals used in the products vary among individuals. Previously only carried out by dermatologists and plastic surgeons, skinpeeling procedures are now being performed by a variety of nonmedical professionals such as cosmetologists and beauticians. Some of these professionals use newly marketed preparations that can be purchased through the mail with inadequate instructions; none have been approved by the FDA as being safe and effective. 8

AHA-containing products vary in the concentration of AHA they contain. The products sold to consumers have an AHA concentration of 10% or less. The concentration of AHA products used by trained cosmetologists may run between 20% and 30%, while those used by doctors can range from 50%–70% and are considered medications. 1, 4, 12 AHAs are widely used for the treatment of hyperkeratotic skin disorders and photodamaged skin. Topical application of AHAs modulates the secretion of cytokines by keratinocytes and the regulation of keratinocyte-derived growth factors, and cytokines might represent a mechanism contributing to their therapeutic effects in disorders like photoaging. 13

Studies of comparative effects of retinoic acid, GA, and a lipophilic derivate of salicylic acid on photodamaged epidermis showed GA almost inactive. 14 Other studies demonstrated that epidermal and dermal hyaluronic acid and collagen gene expression increased in GA-treated skin compared with vehicle-treated controls. There was epidermal and dermal remodeling of the extracellular matrix, and longer treatment may result in collagen deposition as suggested by the measured increase of mRNA. 15

Unlabeled use of drugs provides a realistic therapeutic option. For patients who demand the best and safest treatment, often there is no other treatment option available. With off-label uses, the industry asks why they should be asked for more money. The regulators say they were not asked for additional indication, and the doctor is left holding the bag. 16 Below are some off-label uses of AHA different than the ones approved by the FDA.

Unapproved Uses

Chemical Peelings

Known as chemical exfoliation, the procedure is done in medical offices so doctors can control the process and prevent deep-skin burns from the highly acidic solutions. The chemical peels cause the skin to lose its outer layer, or peel off, revealing a fresher-looking layer of skin. It also helps to remove undesirable signs of skin aging, such as discoloration, roughness, and wrinkling. 1 Skin peeling products typically contain combinations and different concentrations of several acids such as resorcinol, phenol, salicylic acid, lactic acid, trichloroacetic acid, GA, as well as other AHAs.

Stretch Marks

Laser treatment of striae rubra and striae alba with the 585-nm pulsed dye laser and topical treatment of striae rubra with 0.1% tretinoin are proven therapeutic options. Unfortunately, laser treatment is not a good alternative for darker skin types, and the efficacy of tretinoin is low. A study was performed to evaluate the effectiveness of topical application of 20% GA for 12 weeks, comparing it to other products. Histopathologic analysis was performed, and the conclusion was that GA and tretinoin produced similar improvement in the appearance of stretch marks: both are safe and effective with minimal irritation. There is increased epidermal thickness and decreased papillary dermal thickness in treated stretch marks when compared with untreated stretch marks, and elastin content within the reticular and papillary dermis can increase with topical 20% GA combined with 0.05% tretinoin emollient cream therapy. 9

Attractiveness or Repellent Effect on Mosquitoes

Certain human beings are consistently more attractive to mosquitoes than others. A study was performed with samples of animals and humans. The application of lactic acid markedly increased the degree of attractiveness of formerly less attractive human odor samples. There was almost no response to animal odor samples, and they were preferred at the end over those which were originally the most attractive. In contrast to human samples, which contain a high amount of lactate, this compound could not be detected in samples from the other tested mammals; however, when skin emanations from animals were combined with lactic acid, as many mosquitoes responded to animal samples as they did to human odors. All these data demonstrate that olfactory-based host preference of the anthropophilic mosquito Aedes aegypti is to a large extent due to differences in the amount of lactic acid in the odor samples. 17

On the other hand, there are studies on human and mouse skin, such as the one by Shirai et al., 18 showing a repellent effect of L-lactic acid on the mosquito Aedes albopictus, and the repellent effect depended on the concentration of the substance.

Since these insects may be transmitters of diseases, such as yellow fever and dengue fever, this effect must be studied further.

Postinflammatory Hyperpigmentation

Treat ment of postinflammatory hyperpigmentation in patients of Fitzpatrick’s skin types IV, V, and VI is very difficult. Although GA peels are useful for hyperpigmented dyschromia in whites, there are no controlled studies examining their safety and efficacy in dark-complexioned individuals. Burns, et al. 19 in 1997, demonstrated that serial GA peels provide an additional benefit with minimal adverse effects for the treatment of post-inflammatory hyperpigmentation in dark-complexioned individuals.

Ichthyosis, Severe Xeroderma, and Epidermolytic Hyperkeratosis

AHA is used with good results for ichthyosis, severe xeroderma, and epidermolytic hyperkeratosis, alone or in association with other oral or topical drugs. A study was performed with these diseases using two different formulations—a regular and a strong AHA blend cream—compared with a non-AHA moisturizing lotion. Better results were found with the AHA preparations. 20

Confluent and Reticulated Papillomatosis

Two patients with confluent and reticulated papillomatosis responded to oral isotretinoin and 10% lactic acid lotion. 21

Psoriasis

A study was organized to evaluate the efficacy, tolerability, and safety of a GA-containing scalp lotion in conjunction with a betamethasone (17-valerate) for psoriasis. In this study, AHAs were clinically investigated as therapeutic modalities, adjuvant to corticosteroids, to diminish systemic and topical adverse side effects most frequently associated with use of the latter. Twenty patients suffering from scalp psoriasis and other psoriatic conditions were included in a double-blind, split-face clinical study using combinations of a 10% (w/w) GA scalp lotion, placebo lotion (excipients only), and a 0.1% (w/w) betamethasone scalp application applied twice daily without any bandage for a period of 8 weeks. Clinical assessments were carried out by highly experienced physician evaluations based on a four-grade scale before treatment and after 2, 4, 6, and 8 weeks. The results demonstrate the efficacy and tolerability of GA scalp lotions, which was improved when used in conjunction with a 0.1% betamethasone scalp application against scalp psoriasis. 22

Verruca Plana

Borbujo et al. 23 treated 15 children with facial flat warts, who had been submitted to other unsuccessful therapies previously, with 15% GA gel. There was total disappearance of the flat warts in 14 subjects. The authors concluded that because of its effectiveness and few side effects, 15% GA should be a first choice therapy for verruca plana on the face.

Conclusions

Off-label use of drugs is widespread and unavoidable, especially when treating the young, the pregnant, the old, those with cancer, and when dealing with cosmetics. Some of the most striking advances in dermatology have followed the off-label use of drugs.

Delay, hesitancy, or indecision in granting a drug supplementary approval by regulatory entities after it has been peer-reviewed and proven to be clinically effective and safe leads to widespread off-label prescribing and frustrated professionals. 16 Patient satisfaction has been overwhelming for physician-directed skin care, but as the number of products, regimens, and adjuncts increase exponentially, we must emphasize a well founded, scientific approach to an individual patient’s pathology. 24 We hope to see more published data about the still unapproved uses of AHA.

References